Lecture 4 Flashcards
Fill in the blanks; In the hypothalamus there is a combined _______ signal (FGF) and a differentiating signal (___). FGF provides new cells and Shh promotes these to a new identity (______ ______ identity). These cells move anteriorly and differentiate
Proliferating sonic hedgehog anterior progenitor
The mechanism which controls the differentiation of the anterior hypothalamic progenitors is thought to underlie development of many neurons in the tuberal hypothalamus too T or F
T
Lots of different classes of hypothalamic neurons are all born from tuberal hypothalamic progenitors T or F
F – these are hypothalamic stem like cells the multitude of hypothalamic neurons are born from the anterior hypothalamic progenitors
In the spinal cord which neurons differentiate at higher concentrations of sonic hedgehog and where in the neural tube are these derived from
Ventral neural progenitors receive higher levels of sonic hedgehog signalling and become motor and V3 neurons
What is the main sonic hedgehog receptor
Ptc
What is meant by obligate co-receptors in terms of sonic hedgehog
Obligate co-receptors are receptors that also bind sonic hedgehog and are required in order to it to bind to ptc
Give an overview of what is seen in the absence of sonic hedgehog signalling
Ptc is inhibiting smo activity by preventing it from inserting into the membrane. Hence GliA is converted to GliR which therefore can’t upregulate sonic hedgehog target gene transcription
Give an overview of what is seen in the presence of sonic hedgehog signalling
Sonic hedgehog binds to ptc and alleviates the repression of smo by ptc. Smo is hence allowed to insert into the membrane and signal where it prevents the conversion of GliA to GliR. GliA can then translocate to the nucleus and upregulate sonic hedgehog target gene expression
Give some examples of other transmembrane proteins that also bind to sonic hedgehog
Cdo Brother of Cdo Hhip and Gas1
List some of the positive targets of GliA
Ptc1 Ptc2 and Hhip
List some of the negative targets of GliA
Gas1 CDO and BOC
What is significant about the half-life of sonic hedgehog receptors
They are extremely short
Explain ligand dependant antagonism
Ligand dependant antagonism arises due to a complete change in the receptor profile present in the cell membrane as a result of sonic hedgehog signalling. When sonic hedgehog is absent ptc1 Gas1 Cdo and BOC are present in the membrane allowing the cell to respond to subsequent sonic hedgehog ligand. Once the sonic hedgehog signal is present GliA leads to the downregulation of the sonic hedgehog obligate co-receptors Cdo BOC and Gas1 in exchange for increased expression of Ptc1 Ptc2 and Hhip. So now these receptors as well as Smo are present in the membrane however without the presence of the obligate co-receptors the cell is rendered unable to respond to subsequent sonic hedgehog. The cell needs Gas1 CDO and BOC to alleviate Smo repression and hence no matter how much hedgehog ligand is present subsequently the cell will be unable to initiate the signalling pathway
Describe the non-autonomous effects of ligand-dependant antagonism in sonic hedgehog signalling
The altered receptor expression profile on the cell surface changes the way the sonic hedgehog is spreading. In the presence of LDA there will be more sonic hedgehog receptors in the membrane. This means that there is a bigger chance of any sonic hedgehog ligands binding to a receptor closer to the source and thus fewer molecules diffuse further. This means that less sonic hedgehog is available to go further away and bind to receptors. Thus LDA essentially acts to restrict the diffusion gradient of the sonic hedgehog ligand.
